Oxycodone is a semisyntheticopioid synthesized from thebaine, an opioid alkaloid found in the Persian poppy, and one of the many alkaloids found in the opium poppy. It is a moderately potent opioid analgesic, generally indicated for relief of moderate to severe pain.[8] Oxycodone was developed in 1917 in Germany[9][10] as one of several semi-synthetic opioids in an attempt to improve on the existing opioids.[1]

Oxycodone is available as single-ingredient medication in immediate release and controlled release. Parenteral formulations of 10 mg/mL and 50 mg/mL are available in the UK for IV/IM administration.[11] Combination products are also available as immediate-release formulations, with non-narcotic analgesic ingredients such as paracetamol (acetaminophen) and nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen. An abuse-deterrent combination with naloxone is available in managed-release tablets. If injected, the naloxone precipitates opioid withdrawal symptoms and blocks the effect of the medication. It was originally developed in Germany where it is known as dihydroxycodeinone or eukodal.

Oxycodone is a highly addictive opioid chemical very similar to heroin. OxyContin is the brand name of a product that contains oxycodone in a sustained-release pill. Other forms of oxycodone are listed below.

OxyContin is often considered to be ground zero in an opioid crisis across North America. Many of those who died after taking OxyContin were not initially addicts but became addicts after being prescribed the drug by their doctor, and the use of opiates such as oxycodone is a leading cause of death in young adults, according to reports.[12][13][14]

In 2003, the General Accounting Office investigated the marketing of OxyContin and reported that Purdue Pharma distributed an OxyContin video without FDA’s review, that appeared to have made unsubstantiated claims and minimized risks. According to the GAO, the physician in the videos also stated that opioid analgesics have been shown to cause addiction in less than 1 percent of patients — a claim that the FDA said has not been substantiated. In addition, the GAO noted that Purdue has been cited twice by FDA for using advertisements in professional medical journals that violated the FD&C Act.[15]

In 2007, the parent of Purdue Pharma agreed to pay more than $600 million, and three top executives pleaded individually guilty, to settle criminal charges that they misled regulators, doctors and patients about the drug’s risk of addiction and its potential to be abused.[12][16] Attorney General Bob McDonnell was quoted as saying "The criminal behavior in this case embodies a systematic pattern of misrepresentations about the addictive nature of the product by these defendants" and "Purdue Frederick and certain corporate offices, over a period of time, engaged in criminally deceptive behavior which caused OxyContin, a highly addictive drug, to be misbranded".[17]

A 2009 study in the Canadian Medical Association Journal [18] found that "The addition of long-acting oxycodone to the drug formulary was associated with a 5-fold increase in oxycodone-related mortality (p < 0.01) and a 41% increase in overall opioid-related mortality (p = 0.02)".

By 2010, nearly one of every eight deaths (12.1%) among individuals aged 25–34 years in Ontario was opioid-related.[19]

It is clear that the United States is suffering from an epidemic of accidental deaths and addiction resulting from the increased sale and use of powerful narcotic painkillers. According to CDC data, “more than 40% (14,800)” of the “36,500 drug poisoning deaths in 2008” were related to opioid-based prescription painkillers. Deaths from these drugs rose more rapidly, “from about 4,000 to 14,800” between 1999 and 2008, than any other class of drugs, killing more people than heroin and cocaine combined. More people in the United States now die from drugs than car accidents as a result of this new epidemic. Additionally, the CDC reports that improper “use of prescription painkillers costs health insurers up to $72.5 billion annually in direct health care costs.”

See source for additional references. The Committee requested information from Purdue Pharma on any amounts paid to supposedly independent medical organizations funded by industry, saying that “Recent investigative reporting […] revealed extensive ties between companies that manufacture and market opioids and non-profit organizations such as the American Pain Foundation, the American Pain Society, the American Academy of Pain Medicine, the Federation of State Medical Boards, and the University of Wisconsin Pain and Policy Study Group”.[20]

A 2015 CMA policy paper states that the harms associated with psychoactive prescription medicines, particularly opioids, such as oxycodone, hydromorphone and fentanyl, are a significant public health and patient safety issue.[21]

After all of that, in 2016, a research study found no benefit of oxycodone in reducing reported pain. The study was performed to compare whether moderate to severe pain was reported after 6 weeks, among a cohort of 948 victims of motor vehicle crashes when prescribed either opioids or a normal anti-inflammatory such as ibuprofen. There was no statistically significant difference found in the risk of continued pain (risk difference = 7.2%, 95% confidence interval -5.2, 19.5%).[22] However, participants prescribed opioids were more likely to report continued use of prescription opioids medications at week 6 (risk difference = 17.5%, 95% confidence interval 5.8, 29.3%). The lead author, an assistant professor of emergency medicine at Brown University and an ED physician at Rhode Island Hospital, was quoted as saying “You'd think there would be a wealth of studies comparing our 'go-to' pain meds, but there just aren't.”[23]

In summary, oxycodone is a highly addictive opioid essentially similar to heroin, and OxyContin is a sustained-release form of it. It has been cited as the cause of significant social and economic damage, due in part to the actions of a pharmaceutical company that, according to the Assistant U.S. Attorney General, “put its desire to sell OxyContin above the interests of the public” and “misled physicians about the addiction and withdrawal issues involved with Oxycontin” [24]

Oxycodone has been in clinical use since 1916,[1] and it is used for managing moderate to moderately severe acute or chronic pain.[25] It has been found to improve quality of life for those with many types of pain.[26] Experts are divided regarding use for non cancer-related chronic pain, as most opioids have great potential for dependence and may also create paradoxical pain sensitivity.

Oxycodone is available as controlled-release tablet, intended to be taken every 12 hours.[27] A 2006 review found that controlled-release oxycodone is comparable to instant-release oxycodone, morphine, and hydromorphone in management of moderate to severe cancer pain, with fewer side effects than morphine. The author concluded that the controlled release form is a valid alternative to morphine and a first-line treatment for cancer pain.[28] In 2014, the European Association for Palliative Care recommended oral oxycodone as a second-line alternative to oral morphine for cancer pain.[29]

In the US, extended-release oxycodone is approved for use in children as young as 11 years old. The approved indication is for relief of cancer pain, trauma pain, or pain due to major surgery, in children already treated with opioids, who can tolerate at least 20 mg per day of oxycodone; this provides an alternative to Duragesic (fentanyl) the only other extended-release opioidanalgesic approved for children.[30]

In the United States, oxycodone is only approved for oral use, available as tablets and oral solutions. In the United Kingdom, oxycodone is also approved for intravenous (IV) and intramuscular (IM) use. When first introduced in Germany during World War I, IV and IM oxycodone was commonly used for post-operative pain management of Central Powers soldiers.[1]

The risk of experiencing severe withdrawal symptoms is high if a patient has become physically dependent and discontinues oxycodone abruptly. Medically, when the drug has been taken regularly over an extended period, it is withdrawn gradually rather than abruptly. People who regularly use oxycodone recreationally or at higher than prescribed doses are at even higher risk of severe withdrawal symptoms. The symptoms of oxycodone withdrawal, as with other opioids, may include "anxiety, panic attack, nausea, insomnia, muscle pain, muscle weakness, fevers, and other flu-like symptoms".[45]

Withdrawal symptoms have also been reported in newborns whose mothers had been either injecting or orally taking oxycodone during pregnancy.[46]

Ritonavir or lopinavir/ritonavir greatly increase plasma concentrations of oxycodone in healthy human volunteers due to inhibition of CYP3A4 and CYP2D6.[48]Rifampicin greatly reduces plasma concentrations of oxycodone due to strong induction of CYP3A4.[49] There is also a case report of fosphenytoin, a CYP3A4 inducer, dramatically reducing the analgesic effects of oxycodone in a chronic pain patient.[50] Dosage or medication adjustments may be necessary in each case.[48][49][50]

(For lists of CYP3A4 and CYP2D6 inhibitors and inducers, see here and here, respectively.)

In 1997, a group of Australian researchers proposed (based on a study in rats) that oxycodone acts on KORs, unlike morphine, which acts upon MORs.[53] Further research by this group indicated the drug appears to be a κ2b-opioid agonist.[54] However, this conclusion has been disputed, primarily on the basis that oxycodone produces effects that are typical of μ-opioid agonists.[55]

In 2006, research by a Japanese group suggested the effect of oxycodone is mediated by different receptors in different situations. Specifically in diabetic mice, the κ-opioid receptor appears to be involved in the antinociceptive effects of oxycodone,[56] while in nondiabetic mice, the μ1-opioid receptor seems to be primarily responsible for these effects.[57]

After a dose of conventional (instant-release) oral oxycodone, the onset of action is 10–30 minutes,[3][4] and peak plasma levels of the drug are attained within roughly 30–60 minutes;[3][4][58] in contrast, after a dose of OxyContin (an oral controlled-release formulation), peak plasma levels of oxycodone occur in about three hours.[43] The duration of instant-release oxycodone is 3 to 6 hours, although this can be variable depending on the individual.[4]

Oxycodone in the blood is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain.[43] Conventional oral preparations start to reduce pain within 10–15 minutes on an empty stomach; in contrast, OxyContin starts to reduce pain within one hour.[25]

In humans, N-demethylation of oxycodone to noroxycodone by CYP3A4 is the major metabolic pathway, accounting for 45% ± 21% of a dose of oxycodone, while O-demethylation of oxycodone into oxymorphone by CYP2D6 and 6-ketoreduction of oxycodone into 6-oxycodols represent relatively minor metabolic pathways, accounting for 11% ± 6% and 8% ± 6% of a dose of oxycodone, respectively.[4][37]

The first pathway of the above three accounts for 40% of the metabolism of oxymorphone, making oxymorphone-3-glucuronide the main metabolite of oxymorphone, while the latter two pathways account for less than 10% of the metabolism of oxymorphone.[61] After N-demethylation of oxymorphone, noroxymorphone is further glucuronidated to noroxymorphone-3-glucuronide.[61]

A few of the metabolites of oxycodone have also been found to be active as MOR agonists, some of which notably have much higher affinity for (as well as higher efficacy at) the MOR in comparison.[58][62][63] Oxymorphone possesses 3- to 5-fold higher affinity for the MOR than does oxycodone,[4] while noroxycodone and noroxymorphone possess one-third of and 3-fold higher affinity for the MOR, respectively,[4][63] and MOR activation is 5- to 10-fold less with noroxycodone but 2-fold higher with noroxymorphone relative to oxycodone.[60] Noroxycodone, noroxymorphone, and oxymorphone also have longer half-lives than oxycodone.[58][64]

However, in spite of the greater in vitro activity of some of its metabolites, it has been determined that oxycodone itself is responsible for 83.0% and 94.8% of its analgesic effect following oral and intravenous administration, respectively.[62] Oxymorphone plays only a minor role, being responsible for 15.8% and 4.5% of the analgesic effect of oxycodone after oral and intravenous administration, respectively.[62] Although the CYP2D6 genotype and the route of administration result in differential rates of oxymorphone formation, the unchanged parent compound remains the major contributor to the overall analgesic effect of oxycodone.[62] In contrast to oxycodone and oxymorphone, noroxycodone and noroxymorphone, while also potent MOR agonists, poorly cross the blood-brain-barrier into the central nervous system, and for this reason, are only minimally analgesic in comparison.[58][60][62][63] In accordance, while higher CYP2D6 activity increases the effects of oxycodone (due to increased conversion into oxymorphone), higher CYP3A4 activity has the opposite effect, and decreases the effects of oxycodone (due to increased metabolism into noroxycodone and noroxymorphone).[65]

Oxycodone is metabolized by the cytochrome P450 enzyme system in the liver, making it vulnerable to drug interactions.[43] Some people are fast metabolizers, resulting in reduced analgesic effect, but increased adverse effects, while others are slow metabolisers, resulting in increased toxicity without improved analgesia.[66][67] The dose of oxycodone must be reduced in patients with reduced hepatic function.[25]

Oxycodone's chemical name is derived from codeine. The chemical structures are very similar, differing only in that

Oxycodone has a hydroxyl group at carbon-14 (codeine has just a hydrogen in its place)

Oxycodone has a 7,8-dihydro feature. Codeine has a double bond between those two carbons; and

Oxycodone has a carbonyl group (as in ketones) in place of the hydroxyl group of codeine.

It is also similar to hydrocodone, differing only in that it has a hydroxyl group at carbon-14.[25]

Oxycodone is marketed as various salts, most commonly as the hydrochloride salt. The free base conversion ratios of different salts are: hydrochloride (0.896), bitartrate (0.667), tartrate (0.750), camphosulphonate (0.576), pectinate (0.588), phenylpriopionate (0.678), sulphate (0.887), phosphate (0.763), and terephthalate (0.792). The hydrochloride salt is the basis of most American oxycodone products whilst bitartrate, tartrate, pectinate, terephthalate and phosphate salts are also available in European products. Methyiodide and hydroiodide are mentioned in older European publications.

In terms of biosynthesis, oxycodone has been found naturally in nectar extracts from the orchid family Epipactis helleborine; together along with another opioid: 3-{2-{3-{3-benzyloxypropyl}-3-indol, 7,8-didehydro- 4,5-epoxy-3,6-d-morphinan.[72]

Oxycodone and/or its major metabolites may be measured in blood or urine to monitor for clearance, abuse, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Many commercial opiate screening tests cross-react appreciably with oxycodone and its metabolites, but chromatographic techniques can easily distinguish oxycodone from other opiates.[73]

Freund and Speyer of the University of Frankfurt in Germany first synthesized oxycodone from thebaine in 1916,[10] a few years after the German pharmaceutical company Bayer had stopped the mass production of heroin due to hazardous use, harmful use, and dependence. It was hoped that a thebaine-derived drug would retain the analgesic effects of morphine and heroin with less dependence. Unfortunately, this was ultimately not found to be the case.

The first clinical use of the drug was documented in 1917, the year after it was first developed.[10][74] It was first introduced to the US market in May 1939. In early 1928, Merck introduced a combination product containing scopolamine, oxycodone, and ephedrine under the German initials for the ingredients SEE, which was later renamed Scophedal (SCOpolamine ePHEDrine and eukodAL). This combination is essentially an oxycodone analogue of the morphine-based Twilight Sleep, with ephedrine added to reduce circulatory and respiratory effects.[citation needed]

Oxycodone is subject to international conventions on narcotic drugs. In addition, oxycodone is subject to national laws that differ by country. The 1931 Convention for Limiting the Manufacture and Regulating the Distribution of Narcotic Drugs of the League of Nations included oxycodone.[79] The 1961 Single Convention on Narcotic Drugs of the United Nations, which replaced the 1931 convention, categorized oxycodone in Schedule I.[80] Global restrictions on Schedule I drugs include "limit[ing] exclusively to medical and scientific purposes the production, manufacture, export, import, distribution of, trade in, use and possession of" these drugs; "requir[ing] medical prescriptions for the supply or dispensation of [these] drugs to individuals"; and "prevent[ing] the accumulation" of quantities of these drugs "in excess of those required for the normal conduct of business".[80]

Oxycodone is in Schedule I (derived from the Single Convention on Narcotic Drugs) of the Commonwealth's Narcotic Drugs Act 1967.[81] In addition, it is in Schedule 8 of the Australian Standard for the Uniform Scheduling of Drugs and Poisons ("Poisons Standard"), meaning it is a "controlled drug... which should be available for use but require[s] restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence".[82]

In February 2012, Ontario passed legislation to allow the expansion of an already existing drug-tracking system for publicly funded drugs to include those that are privately insured. This database will function to identify and monitor patient’s attempts to seek prescriptions from multiple doctors or retrieve from multiple pharmacies. Other provinces have proposed similar legislation, while some, such as Nova Scotia, have legislation already in effect for monitoring prescription drug use. These changes have coincided with other changes in Ontario’s legislation to target the misuse of painkillers and high addiction rates to drugs such as oxycodone. As of February 29, 2012, Ontario passed legislation delisting oxycodone from the province’s public drug benefit program. This was a first for any province to delist a drug based on addictive properties. The new law prohibits prescriptions for OxyNeo except to certain patients under the Exceptional Access Program including palliative care and in other extenuating circumstances. Patients already prescribed oxycodone will receive coverage for an additional year for OxyNeo, and after that, it will be disallowed unless designated under the exceptional access program.[84]

Much of the legislative activity has stemmed from Purdue Pharma’s decision in 2011 to begin a modification of Oxycontin’s composition to make it more difficult to crush for snorting or injecting. The new formulation, OxyNeo, is intended to be preventative in this regard and retain its effectiveness as a painkiller. Since introducing its Narcotics Safety and Awareness Act, Ontario has committed to focusing on drug addiction, particularly in the monitoring and identification of problem opioid prescriptions, as well as the education of patients, doctors, and pharmacists.[85] This Act, introduced in 2010, commits to the establishment of a unified database to fulfil this intention.[86] Both the public and medical community have received the legislation positively, though concerns about the ramifications of legal changes have been expressed. Because laws are largely provincially regulated, many speculate a national strategy is needed to prevent smuggling across provincial borders from jurisdictions with looser restrictions.[87]

In 2015, Purdue Pharma's abuse-resistant OxyNEO and six generic versions of OxyContin had been on the Canada-wide approved list for prescriptions since 2012. In June 2015, then federal Minister of Health Rona Ambrose announced that within three years all oxycodone products sold in Canada would need to be tamper-resistant. Some experts warned that the generic product manufacturers may not have the technology to achieve that goal, possibly giving Purdue Pharma a monopoly on this opiate.[88]

Several class action suits across Canada have been launched against the Purdue group of companies and affiliates. Claimants argue the pharmaceutical manufacturers did not meet a standard of care and were negligent in doing so. These lawsuits reference earlier judgments in the United States, which held that Purdue was liable for wrongful marketing practices and misbranding. Since 2007, the Purdue companies have paid over $650 million in settling litigation or facing criminal fines.[89]

The drug is in Appendix III of the Narcotics Act (Betäubungsmittelgesetz or BtMG).[90] The law allows only physicians, dentists, and veterinarians (Ärzte, Zahnärzte und Tierärzte) to prescribe oxycodone and the federal government to regulate the prescriptions (e.g., by requiring reporting).[90]

Oxycodone is a restricted drug in Japan. Its import and export is strictly restricted to specially designated organizations having prior permit to import it. In a high-profile case a top Toyota executive, who claimed to be unaware of the law, was arrested for importing oxycodone into Japan.[92][93]

Oxycodone is listed as a Class A drug in the Misuse of Drugs Act of Singapore, which means offences in relation to the drug attract the most severe level of punishment. A conviction for unauthorized manufacture of the drug attracts a minimum sentence of 10 years of imprisonment and corporal punishment of 5 strokes of the cane, and a maximum sentence of life imprisonment or 30 years of imprisonment and 15 strokes of the cane.[94] The minimum and maximum penalties for unauthorized trafficking in the drug are respectively 5 years of imprisonment and 5 strokes of the cane, and 20 years of imprisonment and 15 strokes of the cane.[95]

Oxycodone is a Class A drug under the Misuse of Drugs Act.[96] For Class A drugs, which are "considered to be the most likely to cause harm", possession without a prescription is punishable by up to seven years in prison, an unlimited fine, or both.[97] Dealing of the drug illegally is punishable by up to life imprisonment, an unlimited fine, or both.[97] In addition, oxycodone is a Schedule 2 drug per the Misuse of Drugs Regulations 2001 which "provide certain exemptions from the provisions of the Misuse of Drugs Act 1971".[98]

Under the Controlled Substances Act, enacted in 1971 by President Richard Nixon,[99] oxycodone is a Schedule II controlled substance whether by itself or part of a multi-ingredient medication. The DEA lists oxycodone both for sale and for use in manufacturing other opioids as ACSCN 9143 and in 2013 approved the following annual aggregate manufacturing quotas: 131.5 metric tons for sale, down from 153.75 in 2012, and 10.25 metric tons for conversion, unchanged from the previous year.[100]

Oxycodone, like other opioid analgesics, tends to induce feelings of euphoria, relaxation and reduced anxiety in those who are occasional users.[101] These effects make it one of the most commonly abused pharmaceutical drugs in the United States.[102]

In August 2010, Purdue Pharma reformulated their long-acting oxycodone line, marketed as OxyContin, using a polymer, Intac,[103] to make the pills extremely difficult to crush or dissolve[104] in water to reduce OxyContin abuse.[105] The FDA approved relabeling the reformulated version as abuse-resistant in April 2013.[106]

Pfizer manufactures a preparation of short-acting oxycodone, marketed as OXECTA, which contains inactive ingredients, referred to as tamper-resistant AVERSION® Technology.[107] It does not deter oral abuse. Approved by the FDA in the US in June 2011, the new formulation makes crushing, chewing, snorting, or injecting the opioid impractical because of a change in its chemical properties.[108]

The non-medical use of oxycodone existed from the early 1970s, but by 2015, 91% of a national sample of injecting drug users in Australia had reported using oxycodone, and 27% had injected it in the last six months.[109]

Opioid-related deaths in Ontario had increased by 242% from 1969 to 2014.[110] By 2009 in Ontario there were more deaths from oxycodone overdose than from cocaine overdose.[111] Deaths from opioid pain relievers had increased from 13.7 deaths per million residents in 1991 to 27.2 deaths per million residents in 2004.[112] The abuse of oxycodone in Canada became a problem. Areas where oxycodone is most problematic are Atlantic Canada and Ontario, where its abuse is prevalent in rural towns, and in many smaller to medium-sized cities.[113] Oxycodone is also widely available across Western Canada, but methamphetamine and heroin are more serious problems in the larger cities, while oxycodone is more common in rural towns. Oxycodone is diverted through doctor shopping, prescription forgery, pharmacy theft, and overprescribing.[113][114]

The recent formulations of oxycodone, particularly Purdue Pharma's crush-, chew-, injection- and dissolve-resistant OxyNEO[115] which replaced the banned OxyContin product in Canada in early 2012, have led to a decline in the abuse of this opiate but have increased the abuse of the more potent drug fentanyl.[116] According to a Canadian Centre on Substance Abuse study quoted in Maclean's magazine, there were at least 655 fentanyl-related deaths in Canada in a five-year period.[117]

In Alberta, the Blood Tribe police claimed that from the fall of 2014 through January 2015, oxycodone pills or a lethal fake variation referred to as Oxy 80s[118] containing fentanyl made in illegal labs by members of organized crime were responsible for ten deaths on the Blood Reserve, which is located southwest of Lethbridge, Alberta.[119] Province-wide, approximately 120 Albertans died from fentanyl-related overdoses in 2014.[118]

Abuse and diversion of oxycodone in the UK commenced in the early- to mid-2000s.[120] The first known death due to overdose in the UK occurred in 2002.[121] However, recreational use remains relatively rare.

In the United States, more than 12 million people use opioid drugs recreationally.[122] In 2010, 16,652 deaths were related to opioid overdose in combination with other drugs such as benzodiazepines and alcohol.[123] In September 2013, the FDA released new labeling guidelines for long acting and extended release opioids requiring manufacturers to remove moderate pain as indication for use, instead stating the drug is for "pain severe enough to require daily, around-the-clock, long term opioid treatment."[124] The updated labeling will not restrict physicians from prescribing opioids for moderate, as needed use.[122]

Oxycodone is the most widely recreationally used opioid in America. The US Department of Health and Human Services estimates that about 11 million people in the US consume oxycodone in a non-medical way annually.[125] In 2007, about 42,800 emergency room visits occurred due to "episodes" involving oxycodone.[126] Diverted oxycodone may be taken orally or ingested through insufflation; used intravenously, or the heated vapors inhaled. In 2008, recreational use of oxycodone and hydrocodone were involved in 14,800 deaths. Some of the cases were due to overdoses of the acetaminophen component, resulting in fatal liver damage.[127]

Reformulated OxyContin is causing some recreational users to change to heroin, which is cheaper and easier to obtain.[128]

The International Narcotics Control Board estimated 11.5 short tons (10.4 t) of oxycodone were manufactured worldwide in 1998;[129] by 2007 this figure had grown to 75.2 short tons (68.2 t).[129] United States accounted for 82% of consumption in 2007 at 51.6 short tons (46.8 t). Canada, Germany, Australia and France combined accounted for 13% of consumption in 2007.[129][130] In 2010, 1.3 short tons (1.2 t) of oxycodone were illegally manufactured using a fake pill imprint. This accounted for 0.8% of consumption. These illicit tablets were later seized by the US Drug Enforcement Administration, according to the International Narcotics Control Board.[131] The board also reported 122.5 short tons (111.1 t) manufactured in 2010. This number had decreased from a record high of 135.9 short tons (123.3 t) in 2009.[132]